Abstract
Colorectal cancer (CRC) is the third most common cancer worldwide. In the past decade, mismatch repair deficiency (dMMR), manifested as microsatellite instability-high (MSI-H), has been recognized as a distinct mechanism promoting tumorigenesis in 15% of CRCs including 3% Lynch syndrome and 12% sporadic CRCs. As the molecular classifications of CRCs are continuously evolving, MSI-H CRCs appear to be the most homogeneous CRCs with distinct molecular, morphologic, and clinical features. MSI-H CRCs have dMMR causing MSI-H and genetic hypermutation but with diploid chromosomes. Morphologically, MSI-H CRCs appear as poorly differentiated or mucinous adenocarcinoma with characteristic lymphocytic infiltration. Most importantly, MSI-H CRCs have better stage-adjusted survival, do not respond well to standard 5-fluorouracil–based adjuvant chemotherapy, but do respond to immunotherapy. The United States Food and Drug Administration granted accelerated approval to immune checkpoint inhibitors, anti-programmed cell death protein-1 antibodies pembrolizumab and nivolumab, and the combination of nivolumab with anti-CTLA4 antibody ipilimumab for the second-line treatment of patients with stage IV MSI-H CRCs in 2017. There are still ongoing phase III clinical trials evaluating pembrolizumab and anti-programmed death-ligand 1 antibody atezolizumab as the first-line treatment in stage IV MSI-H CRCs and a phase I study on the combination of nivolumab and ipilimumab in patients with early stage CRC. These ongoing clinical studies on immunotherapy may lead to practice-changing results in the management of MSI-H CRCs. The National Comprehensive Cancer Network 2018 guidelines recommended MSI to be tested in all newly diagnosed CRCs. The MSI test will become increasingly vital in guiding adjuvant chemotherapy and immunotherapy in the management of CRCs.
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